It is increasingly clear that olfactory perception is impaired in a wide variety of neurological and neuropsychiatric disorders. However, this growing clinical appreciation for the human sense of smell is offset by a poor basic understanding of its anatomy and physiology. Even the most fundamental assumptions remain unexplored: Is the human olfactory pathway really ipsilateral? Where exactly is primary olfactory cortex? How fast is odor information transmitted through the human olfactory brain? The major aim of this exploratory research project is to investigate odor-evoked patterns of electroencephalographic (EEG) activity directly from the surface of the human brain in patients with medically intractable epilepsy and to map the olfactory cortex with electrical cortical stimulation and cortico-cortical evoked potentials. The highly accurate placement of a high-density invasive electrode array around the temporal and orbitofrontal cortices during standard surgical exploration offers a unique window into the functional anatomy of the olfactory system which has been largely unexplored. Work proposed here will yield a more comprehensive basic understanding of human olfaction, help in diagnosis and prediction of functional outcome in epilepsy patients, and open up new avenues for monitoring disease onset and progression in other neurological disorders involving the sense of smell. PUBLIC HEALTH RELEVANCE: Abnormalities in the sense of smell have particular clinical relevance for a wide variety of neurological and neuropsychiatric disorders, including complex partial epilepsy, Alzheimer's disease, Parkinson's disease, and schizophrenia. In many instances, perceptual deficits of odor discrimination arise early in the course of illness, likely due to the initial accumulation of neuropathological lesions in olfactory limbic regions of the brain. In combining electrocorticography techniques with olfactory psychophysical approaches in patients with medically refractory epilepsy, the proposed research offers a unique window into the fundamental organization of the human olfactory system. Findings from this work may directly guide the development of new tools for lesion localization in epilepsy and for the prediction of functional outcome in epilepsy patients who are being considered for surgical intervention. The work proposed here will additionally provide new insights into monitoring onset and progression of other neurological diseases in which olfactory perceptual impairments are an early sign.